New Blood Vessel Growth Prevented In Mice with Wet AMD

August 21, 2014

There’s been a major discovery from Washington University in St. Louis (WUSTL). In mice studies, researchers have shown that fibroblast growth factor (FGF) proteins, a family of "signaling proteins" involved in tissue formation, can be independently manipulated to bring about desired results in individual organs without disrupting the organism as a whole.

Shown at top, normal blood vessels in a mouse retina; below, a retina affected by AMD. As AMD worsens, the retina perceives it as “injury” and responds by growing new, leaky blood vessels, which causes further damage as well as distorts and destroys vision. The new study suggests that inhibiting FGF signaling in the eye may help prevent new blood vessel formation. Images Courtesy of Washington University in St. Louis.

While limited to mice, the results are potentially good news for humans suffering from certain conditions, including wet macular degeneration and slow wound healing from diabetes. FGF proteins are involved in embryonic development and also are critical players in blood vessel formation and wound healing. When an organ is injured, the healing process triggers blood vessel formation (angiogenesis) to nourish and regrow tissue at the injury site. With poorly controlled diabetes, healing can be compromised, and slow healing in some wounds, such as foot ulcers, leads to amputation.

What the Apte and Ornitz labs were able to show, collaboratively was that, on one hand, upping FGF improved wound healing in mice models of diabetes, while on the other hand, inhibiting FGF helped prevent choroidal neovascularization (CNS), the out-of-control growth of fragile, leaky blood vessels that distort vision and damage the retina, which is seen in both diabetic retinopathy and “wet” forms of age-related macular degeneration (AMD). In the advanced, “wet” stage of AMD, it’s believed that the retina, too, is responding to inflammation and other factors it “reads” as injury by forming new blood vessels—but in this case, the vessel growth harms, rather than heals, the eye.

To carry out their role in angiogenesis, FGF proteins bind with specific receptor molecules, FGFRs, located on the surface of many cell types. In their mice experiments, rather than to completely shut down FGFRs, Apte and Ornitz selectively manipulated their expression for two specific FGF proteins involved in formation of cells that line the interior of blood vessels and create new vasculature. Research had already suggested that these FGF pathways are not involved with normal development and tissue maintenance, and thus that healthy tissue would not likely be affected.

The results showed that to be true. Mice engineered to lack the targeted receptors were shown, once injured, to have fewer blood vessels surrounding the injury site and to heal more slowly than their normal littermates. In other respects, including longevity, they were normal.

“That’s an important point,” Dr. Apte was quoted in a WUSTL press release. “With any targeted therapy, we worry about damaging the normal vessels. But our work suggests that inhibiting FGF signaling in the eye may prevent this abnormal response without harming normal vessels.”

Ongoing plans call for the Apte lab to forge connections between this latest discovery and their ongoing investigation of the role that macrophage cells play in AMD—results were published by him and two members of his lab, Abdoulaye Sene, PhD (first author), and Rae Nakamura, PhD, in Cell Metabolism last year (2013), and summarized in our News Update. Sene and Nakamura are also coauthors on the PNAS report.

Interview with Rajendra Apte, MD, PhD

Dr. Apte responds to our questions about the team’s latest work.

Rajendra Apte (right) and Abdoulaye Sene at ARVO last May.

Q. What led to this discovery, and how long has your lab been working on the problem?A. We have always been interested in the vascular and healing responses associated with neovascularization in the eye. FGF and vascular endothelial growth factor (VEGF) have been involved in these processes. Although VEGF has been studied extensively, the role of FGF signaling in the eye was unclear. It is also interesting to see that the FGF response seems to be independent of VEGF.

Q. How can you shut off FGF signaling in the eye without adverse effects on other vessels and/or wound healing elsewhere in the body?A. These studies show that FGF signaling seems to be important not in development or vascular homeostasis but in pathogenic neovascularization and injury response. As such, targeting this pathway effectively may spare normal vasculature.

Q. What are the chances that this approach will work in humans with wet AMD? Is the vasculature of the mouse eye similar, and do these findings lend hope? A. It is always important to remember that ‘mice and humans’ are not identical, although they share a large part of the genome. The promise of this work is that FGF directed therapies are already in use or under investigation for conditions outside the eye.

Q. Any idea as to what such a therapy might entail (injections?) or too preliminary to speculate?A. It is too early to speculate but I do think any approach would have to be local and targeted.

Q. Have you studied what triggers FGF expression in AMD—is there macrophage involvement that would tie in your earlier work?A. Great question—we are actively looking at these signaling pathways. This will be important in identifying additional therapeutic pathways.

Q. Would you care to speculate as to where the inflammatory/immune pathology starts in AMD? In the retinal pigmented epithelium (RPE), as many have suggested? Mediated by drusen? Or another speculative mechanism?A. As you know, everyone has a different take on this. I think all the cells that you have mentioned play a role and it is more like a cascade with several amplification loops. My personal bias is to understand the biology, however complex it may be. Some investigators get too hung up on their favorite hypothesis and forget the big picture.

Q. What provokes the crossover from dry to wet AMD, in other words, where does the insult/injury occur? Can you share insights?A. Again, very complex, but it is clear that signals at the Bruchs membrane/RPE interface are critical in disease progression. I think we and others have shown that lipids in drusen induce inflammation and may be the key to disease progression.

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